Gunfire rang out shortly before sunrise at the prison in the city of Bukavu, residents said, and the inmates managed to force their way through the main gate a short while later.
"We have just finished the tally, there were a total of 301 escapees, but 35 have already been recaptured," a police officer told AFP, requesting anonymity.
"The provisional toll this afternoon is two dead, a civilian and a soldier, and seven injured including three civilians and four soldiers."
Descartes Mponge, president of the South Kivu Civil Society organisation, told AFP there were "at least 1,600 prisoners in this prison" at the time of the breakout.
Large numbers of police and soldiers surrounded the prison after the escape, disrupting daily life in nearby suburbs.
"As children are preparing for exams, this awakening to gunfire really worries us," said a teacher at an examination centre where final tests were due to take place today.
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